Cannabinoids isolated from Cannabis sativa have been recognized for centuries as therapeutic agents. For example, they have been utilized for analgesia, muscle relaxation, appetite stimulation, and anti-convulsion. Recent studies also indicate their potential therapeutic effects in treating cancer and alleviating the symptoms of chronic inflammatory diseases, such as rheumatism and multiple sclerosis.
The actions of cannabinoids are mediated by at least two types of cannabinoid receptors, CB1 and CB2 receptors, both of which belong to the G-protein-coupled receptor (GPCR) superfamily. The CB1 receptor is predominantly expressed in the brain to mediate inhibition of transmitter release and the CB2 receptor is primarily expressed in immune cells to modulate immune response. See Matsuda et al., Nature (1990) 346:561 and Munro et al., Nature (1993) 365:61.
Compared to other GPCRs, the CB1 receptor is typically expressed at higher levels. In the central nervous system, it is highly expressed in the cerebral cortex, hippocampus, basal ganglia, and the cerebellum, but has relatively low levels in the hypothalamus and the spinal cord. See, e.g., Howlett et al., Pharmacol Rev (2002) 54:161. Its functions affect many neurological and psychological phenomena, such as mood, appetite, emesis control, memory, spatial coordination of muscle tone, and analgesia. See, e.g., Goutopoulos et al., Pharmacol Ther (2002) 95:103. In addition to the central nervous system, the CB1 receptor is also present in several peripheral organs, such as the gut, heart, lungs, uterus, ovary, testis, and tonsils. See, e.g., Galiègue et al., Eur J Biochem (1995) 232:54.
The CB2 receptor is 44% identical to the CB1 receptor with a 68% identity in the trans-membrane regions. See Munro et al., Nature (1993) 365:61. Compared to the CB1 receptor, the CB2 receptor has a more limited distribution with a high expression in the spleen and tonsils, and a low expression in the lungs, uterus, pancreas, bone marrow, and thymus. Among immune cells, B cells express the CB2 receptor at the highest level, followed in order by natural killer cells, monocytes, polymorphonuclear neutrophils, and T lymphocytes. See Galiègue et al., Eur J Biochem (1995) 232:54. Activation of CB2 receptors has been shown to have analgesic effects in inflammatory models involved in neurodegeneration diseases (such as Alzheimer's disease), and play a role in the maintenance of bone density and progression of atherosclerotic lesions. See, e.g., Malan et al., Pain (2001) 93:239; Benito et al., J Neurosci (2003) 23:11136; Ibrahim et al., Proc Natl Acad Sci USA (2003) 100:10529; Idris et al., Nat Med (2005) 11:774; and Steffens et al., Nature (2005) 434:782.